Techniques such as magnetic resonance (MR) scanning, computerised tomography (CT) scanning and ultrasound scanning are widely used diagnostic tools for a wide range of medical investigations.
For instance, the potential use of computed tomography (CT) for the assessment of myocardial perfusion has long been recognised. However, only recently has the advent of fast multi-slice CT technology resulted in potential widespread clinical application. The most prevalent method of CT perfusion (CTP) is a single time point comparison of myocardial contrast densities at rest and under pharmacological stress.
Myocardial perfusion is a major determinant of cardiovascular risk and is an essential tool for the guidance of interventional strategies. Magnetic resonance perfusion (MRP) represents a highly accurate clinical perfusion imaging technology, with higher spatial resolution than single photon emission computed tomography (SPECT) and excellent correlation with invasive fractional flow reserve (FFR) data.
First-pass myocardial MR perfusion has become a reliable tool for the diagnosis of myocardial ischemia. Although myocardial perfusion MR images are usually evaluated by visual assessment or by semi-quantitative approaches, quantitative analysis and absolute quantification have also been described and may permit a more accurate assessment of patients with heart disease, particularly those with three-vessel coronary artery disease. Quantitative analysis was initially proposed more than a decade ago and has achieved a recognized role as an investigational tool. However, it has not been adopted into clinical routine thus far. One of the main reasons is the lack of standardization of the analysis methods which is partly due to the lack of a gold standard for validation of the results. Novel techniques are currently developed using combinations of numerical simulations, animal studies and human trials.
Synthetic data simulate the arterial input function (AIF) and myocardial signal intensity (SI) curves at different perfusion rates. Such simulations are intended as benchmarks for deconvolution methods under controlled conditions and known simulated perfusion rates. Though extensively used in the past, these simulations lack standardization and vary from one study to another, hampering comparison of the results between different sites. Furthermore, simulated data do not completely address scanning artefacts (like saturation or susceptibility effects) and ignore spatial relations within the images. Moreover, the level of noise in the data is simulated as well. While simulations allow isolation of the deconvolution problem, they could lead to the development of analysis methods that are not applicable to a real-world scenario. Moreover, no gold standard validation is available and the development of new sequences or novel MR hardware is precluded.
To partially overcome these limitations, vials containing water and Gadolinium in different concentrations have been used to acquire MR perfusion images and calculate signal-to-noise ratio and signal saturation for different spin-lattice relaxation time (T1) values of the samples (Ferreira et al., Magn Reson Med 2008, 60, 860-897; Ishida et al., J Magn. Reson Imaging 2009:29:205-210).
These methods allow the acquisition of real MR data, testing and comparing novel sequences and hardware. However, the SI curves reconstructed from the images result from simulations and quantitative results lack validation against true perfusion measurements. Finally, these static phantoms do not allow the comparison between different schemes of contrast agent injection and do not allow any simulation of the relevant physiological parameters.
Recently, a dynamic flow-imaging phantom has been described to provide reproducibility assessment and validation of dynamic contrast enhanced computed tomography (CT) (Driscoll et al., Med Phys. (2011) 38 (8)). This system, which is potentially MR compatible, mimics realistic time attenuation curves by modulating a contrast injection pump and the ratio between the flow in the main circuit and in a compartment providing a simulation of the tissue response curve. In this study, the CT flow phantom was validated using mathematical models including the control parameters of the system rather than by measuring the flow across the sections of the circuit and the aim was to produce reproducible time attenuation curves for the comparison and assessment of the reproducibility using different CT scanners. The validation of quantitative perfusion measurements was not the main purpose of the CT flow phantom.
A further phantom described in US2009/0316972 uses microengineering to produce a complex model of the microvascular system, useful for the characterisation of perfusion in microvascular networks.
Animal experiments have been used to validate semi-quantitative and true quantitative assessments of myocardial perfusion. These models offer realistic and physiological generation of the signal and allow invasive procedures, such as microspheres injection, for validation of the results. However, the high costs and ethical and logistic considerations limit their applicability.
To overcome these limitations in part, some novel preclinical models have been recently developed. Makowski et al (Magn Reson Med 2010; 64:1592-1598) have described a method of performing first-pass MR perfusion imaging in rodents, using the k-t principal component analysis techniques and a clinical 3T MR scanner. The availability of many transgenic models of cardiovascular disease makes this method particularly useful. However, issues of animal usage remain.
Schuster et al. (J. Cardiovascular Magn Reson 2010; 12; 53) have also described a novel explanted and blood perfused pig heart MR compatible model to develop and validate perfusion acquisitions. This model offers much greater control over physiological parameters and better reproducibility compared with in-vivo preparations although it is less physiological. This isolated pig heart model can be studied in a clinical scanner. In addition, the porcine heart is of comparable dimensions to a human heart. These factors facilitate the development, validation and translation of new perfusion methods. However, operating this experimental model in a clinical scanner is associated with higher costs and requires considerable preparation times, and will therefore probably be restricted to the validation of pre-developed methodology.
Human studies should in theory offer the best setup for the validation of novel MR perfusion methods. Though several studies have been performed comparing the diagnostic accuracy of MR perfusion with coronary angiography and fractional flow reserve (FFR) assessment, the validation of quantitative perfusion assessment can only be performed by comparing these methods in a randomised controlled clinical trial with a measure of outcomes.
There is a need for perfusion phantom hardware capable of simulating the process of first pass perfusion in a highly controllable and reproducible way and thus provide true physical validation of quantitative perfusion methodologies such as MR and CT.
The applicants have devised a device that reproduces physiological features in a simple manner that allows perfusion studies to be carried out in a consistent manner, to allow for modelling by techniques such as MRI and CT.